Linezolid, with a chemical name of (S)—N-{[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide, is a new oxazolidinone antibiotic drug developed by Pharmacia & Upjohn. It was first marketed in the United States in April of 2000 under the commercial name of Zyvox for treating pneumonia and complicated skin infection caused by methicillin-resistant Staphylococcus aureus (MRSA), and bacteremia caused by vancomycin-resistant enterococci (VREF) or penicillin-resistant Streptococcus pneumoniae (PRSP).
At present, methods for synthesis of linezolid have been described in the literature [(1) Chen W, Hu J L, Zhang X X. Graphical Synthetic Routes of Linezolid. Chinese Journal of Pharmaceuticals, 2010, 41(1): 62-63; (2) He B, Zhang Y. The Synthesis of Oxazolidinone Antibiotics [J]. World Notes on Antibiotics, 2009, 30(2): 82-88]. The better methods include: (1) Reacting (S)-epichlorohydrin and benzaldehyde in aqueous ammonia, and hydrolyzing the resulting imine by hydrochloric acid to obtain (2S)-1-amino-3-chloro-2-propanol, to which a diacetyl group is introduced by acetylation. The product is then condensed with N-carbobenzoxy-3-fluoro-4-morpholinyl-aniline under the action of anhydrous lithium tert-butoxide to give linezolid. The yield of Linezolid is about 50%. The raw materials used are readily available and fewer steps are involved. However, this method requires using anhydrous lithium tert-butoxide which is expensive and hygroscopic [Perrault W R, Pearlman B A, Godrej D B et al. The synthesis of N-aryl-5(S)-aminomethyl-2-oxazolidinone antibacterials and derivatives in one step from aryl carbamates. Org Process Res Dev, 2003, 7(4): 533-546]; (2) Reacting (S)-glycidyl butyrate and N-carbobenzoxy-3-fluoro-4-morpholinyl-aniline with butyl lithium at 78° C. to give (S)-3-(3-fluoro-4-morpholinephenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one, which is reacted with methanesulfonic acid and azide, and then reduced and acetylated to give linezolid. [Brickner S J, Hutchinson D K, Barbachyn M R, et al. Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections. J Med Chem, 1996, 39(3): 673-679]. This method involves more steps and stringent reaction conditions, and requires explosive sodium azide. (3) Condensation between 3-fluoro-4-morpholinylphenyl isocyanate and (S)-glycidyl butyrate under the action of lithium bromide and tributylphosphine oxide to obtain the nucleus of (S)-oxazolidinone, which is further converted to Linezolid [Huang Q, Li H, Niu P L et al., Method for preparing (R)—N-(3-fluoro-4-morpholinylphenyl)-oxazoline-5-methanol, CN1772750]. This method involves more steps and expensive raw materials but only achieves a relatively low yield; (4) Reacting 3-fluoro-4-(morpholinyl)bromobenzene and 5-[(S)-(1-phenylethyl)aminomethyl]-(1,3-oxazolidin-2-one) under the action of cuprous iodide, followed by the Ullmann coupling reaction, catalytic hydrogenolysis and acetylation to give linezolid. [Ramallal R M, Liz R, Gotor V. Regio selective and stereo specific synthesis of enantiopure 1,3-oxazolidin-2-ones by intramolecular ring opening of 2-(Boc-amino methyl)aziridines. preparation of the antibiotic linezolid. Org Lett, 2008, 10(10): 1935-1938]. The raw materials used in this method are not readily available and the reaction conditions are stringent.
In summary, the disclosed methods of synthesizing linezolid are limited by their ability to mass produce linezolid due to the relatively high cost as a result of raw materials that are expensive or not readily available, stringent reaction conditions; a large number of reaction steps, low overall yield; production of large amounts of liquid, solid and gaseous wastes during the preparation process; and reactions that require cumbersome operation and follow-up. Therefore, new methods that use cheap and readily available raw materials, require mild reaction conditions and simple operation, achieve high chemical yield and optical purity, and environmentally friendly are needed for the synthesis of linezolid.